The NFκB family of transcription factors plays a pivotal role in inflammation and immune responses, proliferation, apoptosis and expression of certain viral genes. Therefore, the NFκB signaling pathway has also provided a focus for pharmacological intervention, primarily in chronic inflammation or in cancer, where the pathway is often constitutively active and plays a role in the disease.
The two most common pathways are the canonical (or classical) and the non-canonical (or alternative) pathways. A functional NFκB molecule is a heterodimer composed of members of the Rel family of proteins, which includes Rel A (p65), c-Rel, p50 in the classical pathway and Rel B and p52 in the alternative pathway. The major form of NFκB that is rapidly induced after stimulation is the Rel A/p50 complex. NFκB is maintained in an inactive form in the cytoplasm by IκB, which binds to NFκB and masks its nuclear localization signal.
There are several IκB proteins that are differentially regulated and have various affinities for individual NFκB complexes. IκBα is the best characterized. It is phosphorylated by the IκB kinase complex (IKK), resulting in its subsequent degradation by the proteasome and release of NFκB. NFκB is then able to translocate to the nucleus where it stimulates the transcription of a wide variety of genes, including cytokines, cell adhesion molecules and acute phase response proteins, which are involved in proliferation and survival as well as the inflammatory response. In the alternative pathway, activation of IKKα phosphorylates the NFκB precursor (p100) leading to its proteasomal processing and the formation of the active p52/Rel B heterodimer.